Ndfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease

Foxp3(+) T regulatory (T(reg)) cells suppress immune cell activation and establish normal immune homeostasis. How T(reg) cells maintain their identity is not completely understood. Here we show that Ndfip1, a coactivator of Nedd4-family E3 ubiquitin ligases, is required for T(reg) cell stability and function. Ndfip1 deletion in T(reg) cells results in autoinflammatory disease. Ndfip1-deficient T(reg) cells are highly proliferative and are more likely to lose Foxp3 expression to become IL-4-producing T(H)2 effector cells. Proteomic analyses indicate altered metabolic signature of Ndfip1-deficient T(reg) cells and metabolic profiling reveals elevated glycolysis and increased mTORC1 signalling. Ndfip1 restricts T(reg) cell metabolism and IL-4 production via distinct mechanisms, as IL-4 deficiency does not prevent hyperproliferation or elevated mTORC1 signalling in Ndfip1-deficient T(reg) cells. Thus, Ndfip1 preserves T(reg) lineage stability and immune homeostasis by preventing the expansion of highly proliferative and metabolically active T(reg) cells and by preventing pathological secretion of IL-4 from T(reg) cells.